Alzheimer's disease (AD) is the most common neurodegenerative disease that causes dementia and has neuronal loss and cognitive disorder as progressive neurodegenerative disease symptoms (Donev et al., J Cell Mol Med, 13:4329-48, 2009). The AD has neuropathological features of extracellular amyloid-β (Aβ) plaques and intracellular nerve fiber tangles (Querfurth et al., N Engl J Med. 362(4):329-44; LaFerla et al., Biochem Soc Trans. 38(4):993-5). The amyloid-β is generated by continuous division of an amyloid-β precursor protein (APP), which is mediated by beta-secretase 1 (BACE1) and presenilin/γ-secretase. Generation and aggregation of the amyloid-β play an important role to trigger a complex pathologic induction that causes neurodegeneration, entanglement of nerve fibers, inflammation and loss of neurons.
Activation of microneuroglial cells expressing neuroinflammation is another pathologic characteristic in the brain of a patient with the AD (McGeer et al., Neurosci Lett, 79:195-200, 1987). Further, the microneuroglial cells serve as latent pathogenic origins in many central nervous system (CNS) diseases including chronic neurodegenerative diseases such as AD, Parkinson's disease (PD), human immunodeficiency virus (HIV) dementia, and multiple sclerosis (Block et al., Nat Rev Neurosci, 8:57-69, 2007). The activated microneuroglial cells and leukocytes produce various inflammation mediators including anaphylatoxin complement, cytokine, chemokine, and prostaglandin (Gelderblom et al., Stroke 40(5):1849-57, 2009; Iadecola et al., Nature Neuroscience 14(11):1363-1368, 2011).
Studies on an inflammasome complex in peripheral tissues relate to production, secretion, and apoptotic and pyroptotic cell death of inflammatory cytokines (Lamkanfi et al., Annu Rev Cell Dev Biol. 28:137-61). NACHT, LRR and PYD domains-containing protein 1 (NLRP1) and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasomes are cytoplasmic polymer complexes consisting of a NLRP1/3 receptor, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), procaspase-1, procaspase-11 (homology with human procaspase-4 or 5), and X-linked inhibitor of apoptosis (XIAP) (Boyden et al., Nat Genet 38(2):240-4, 2006; Martinon et al., Mol Cell 10(2):417-26, 2002). The procaspase-1 is automatically activated by activation and homo-oligomerization of NLRP1 and NLRP3 receptors to be converted into the cleaved caspase-1 and form NLRP1 and NLRP3 inflammasomes (Lamkanfi et al., Annu Rev Cell Dev Biol. 28:137-61; Martinon et al., Mol Cell 10(2):417-26, 2002). Chronic accumulation of Aβ promotes activation of the microneuroglial cells in the AD (Goldmann et al., Cell Res. 23:595-6). An increase in IL-1β level is associated with the accumulation of Aβ (Lucin et al., Neuron, 64:110-22, 2009), and IL-1β is produced in an inactive pro-form for activation and secretion of caspase-1, and the activity of caspase-1 is regulated by the inflammasome. The NLRP3 inflammasome detects inflammatory crystal and aggregated proteins such as Aβ and is associated with chronic inflammatory diseases (Halle et al., Nat Immunol 9(8)857-65, 2008; Martinon et al., Annu Rev Immunol 27:229-65, 2009; Heneka et al., Nature 493(7434):674-8). An inflammatory substance induced by the activation of the NLRP inflammasome serves to mediate synaptic dysfunction, cognitive disorder, functional restriction of microneuroglial cells, and the like. The progression of the AD may be efficiently hindered by treatment of inhibiting activation of the NLRP inflammasomes and inflammasome-derived cytokines that play an important role in an Aβ-mediated inflammatory response.
Ramalin has an anti-oxidation effect at a concentration that cytotoxicity is almost not shown in human keratinocytes and fibroblasts (Paudel et al., Phytomedicine. 18(14):1285-90) and is known as an antioxidant that inhibits an inflammatory response.
The present inventors isolate Ramalin which is a novel compound from Ramalina terebrata which is a lichen that grows wild in King George Island, Antarctica in previous studies (Korea Patent No. 10-1025612), and provide a synthesis method of Ramalin (Korea Patent No. 10-1182334). In addition, an effect of preventing or treating inflammation or immunological diseases by the isolated and synthesized Ramalin (Korea Patent No. 10-1290745) and an effect of preventing or treating liver fibrosis and liver cirrhosis by the isolated and synthesized Ramalin (Korea Patent No. 10-1326256) have been found. However, an effect of preventing or treating neurodegenerative diseases by Ramalin has been not yet known.
Accordingly, the present inventors made all efforts to develop effective strategies for the treatment of AD and AD-like diseases, and as a result, confirmed that Ramalin inhibited BACE1 expression and expression of an inflammatory marker such as an NLRP inflammasome protein to inhibit production of amyloid and significantly improve a cognitive function in a AD model mouse and completed the present disclosure.